SUMMARY With this proposal and the future research supported by its findings, we propose to test the hypothesis that early life, ante- and postnatal exposures are risk factors for eosinophilic esophagitis (EoE), particularly in genetically susceptible individuals. The central hypothesis is that risk of EoE is determined by complex interactions between early-life exposures and susceptibility genes with demonstrated functionality in gene and immune regulation The underlying concept of this work it that early life, ante- and postnatal exposures ? known to disrupt colonization of gut microbiota and believed to alter immune development ? are risk factors for EoE, particularly in genetically-susceptible individuals. This study builds on early evidence we have generated from single center, case control studies suggesting that certain early life exposures (antibiotic use in infancy, preterm delivery, Cesarean delivery, neonatal intensive care unit admission, pet exposure and breastfeeding) are associated with increased risk of EoE and that certain susceptibility genotypes (TSLP at 5q22 [rs3806932], the LOC283710 and KLF13 region at 15q13 [rs4329885], and CAPN14 [rs6736278]), interact with early life exposures to modify risk. The present study uses a population-based, case-control study with complete case ascertainment of EoE cases to build on this early evidence. Specifically, the proposed research project includes: Aim 1, a population-based registry-linkage study of early life factors and EoE for data collected prospectively, using population-based registries to characterize cases and controls, measure primary exposures, and potential confounders; Aim 2, a focused gene-environment interaction study informed by previous research on susceptibility SNPs and early life factors associated with EoE; and Aim 3, an evaluation of genetic load and genetic load in interaction with early life factors as a means of assessing genotype in context of phenotypic heterogeneity in disease and identifying possible novel loci implicated in disease pathogenesis. These analyses will not only provide evidence to address the aims outlined, but will also inform future, consortium-based studies of gene-environment interaction in EoE. The research team includes experts in pediatric epidemiology (Jensen), genetic epidemiology (Langefeld and Martin), EoE (Dellon), and immunology and the genetics of EoE (Rothenberg and Kottyan). The research will bring together a unique set of national and international resources and expertise.